Since all of the major Aβ peptide variants, including the pathogenic Aβ42 as known in the art, are ultimately generated by gamma-secretase-mediated proteolysis of APP-C99 (i.e., the beta-secretase-mediated cleavage product of the amyloid protein precursor |APP|), one approach to therapeutic intervention (e.g., intervention in Alzheimer's Disease, AD) relates to lowering total Aβ peptide production by inhibiting the catalytic activity of gamma-secretase. However, gamma-secretase catalyzes the proteolysis of a large number of membrane proteins including the Notch receptor which yields the Notch intracellular domain (NICD), a peptide necessary for proper cellular differentiation and development. Nonetheless, many inhibitors of gamma-secretase activity, generally referred to as gamma-secretase inhibitors (GSIs), have been discovered, and some are being developed clinically. See e.g., Coric, V. et al., 2012, Arch Neurol. 69:1430-1440.
Without wishing to be bound by theory, it is believed that GSIs have the liability of adverse events resulting from (at least in part) the inhibition of Notch proteolysis. See e.g., Wakabayashi T. & De Strooper, B., 2008, Physiology 23:194-204; Fleisher A. S., et al., 2008, Arch Neurol. 65:1031-1038. In addition, gamma-secretase is now known to hydrolyze a rather large number of type I membrane proteins (Wakabayashi & De Strooper, 2008, Id.), implying participation in critical membrane protein degradation and signaling pathway(s). Therefore, inhibiting this enzymatic complex, which has been described as the “proteosome of the membrane” (Kopan, R. & Ilagan, M. X., 2004, Nat. Rev. Mal Cell. Biol. 5:486-488), may in fact be detrimental to an aged AD population with an already compromised neuronal catabolism. Thus, as is the case for other age-related degenerative disorders (e.g., cardiovascular disease), successful disease modifying therapeutic approaches will require long term administration, beginning early in the disease process and with either very tolerable or without side effects.
Recently, an approach utilized NSAID-like substrate-targeted GSMs (i.e., tarenflurbil) which have been shown to selectively inhibit Aβ42 (at least in vitro); however, their poor potency combined with their inability to cross the blood brain barrier resulted in a lack of efficacy in the clinic. See e.g., Kukar, T. L., et al., 2008, Nature 453:925-929; Green, R. C., et al. 2009, J. Amer. Med. Asso. 302:2557-2564; see also Cheng, S., et al., 2007, U.S. Pat. No. 7,244,939; Kounnas, M. Z. et al., 2010, Neuron 67:769-780. Assays useful in characterizing the GSMs and GSIs have been described previously. See e.g., Cheng, S., et al., 2007, Id.; Kounnas, M. Z. et al., 2010, Id.) Certain GSMs have been shown to be potent and efficacious in vivo for lowering the levels of Aβ42 and Aβ40 in both the plasma and brain of APP transgenic mice and chronic efficacy studies revealed dramatically attenuated AD-like pathology in the Tg2576 APP transgenic mouse model.
The poor aqueous solubilities of the earlier GSMs have hindered the necessary preclinical development required for an investigational new drug (IND) application. Thus, there remains a need in the art for safe and effective GSM's. The present application provides solutions to these problems.